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Mitochondrial DNA Copy Numbers in Pyramidal Neurons Are Decreased Virginia Commonwealth University VCU Scholars Compass Neurology Publications Dept. of Neurology 2014 Mitochondrial DNA Copy Numbers in Pyramidal Neurons are Decreased and Mitochondrial Biogenesis Transcriptome Signaling is Disrupted in Alzheimer’s Disease Hippocampi Ann C. Rice Virginia Commonwealth University, [email protected] Paula M. Keeney Virginia Commonwealth University, [email protected] Norah K. Algarzae Virginia Commonwealth University See next page for additional authors Follow this and additional works at: http://scholarscompass.vcu.edu/neurology_pubs Part of the Neurology Commons © 2014 IOS Press and the authors. This is the author’s version of a work that was accepted for publication in Journal of Alzheimer's Disease, vol. 40 iss. 2 (2014) 319–330. The final publication is available at http://dx.doi.org/10.3233/ JAD-131715. Downloaded from http://scholarscompass.vcu.edu/neurology_pubs/6 This Article is brought to you for free and open access by the Dept. of Neurology at VCU Scholars Compass. It has been accepted for inclusion in Neurology Publications by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Authors Ann C. Rice, Paula M. Keeney, Norah K. Algarzae, Amy C. Ladd, Ravindar R. Thomas, and James P. Bennett This article is available at VCU Scholars Compass: http://scholarscompass.vcu.edu/neurology_pubs/6 Mitochondrial DNA Copy Numbers in Pyramidal Neurons are Decreased and Mitochondrial Biogenesis Transcriptome Signaling is Disrupted in Alzheimer’s Disease Hippocampi Ann C. Rice1,2*, Paula M. Keeney1, Norah K. Algarzae1, Amy C. Ladd1, Ravindar R. Thomas1 and James P. Bennett, Jr.1,2,3,4 1Parkinson’s Disease Center, Departments of 2Neurology, 3Psychiatry and 4Physiology and Biophysics Virginia Commonwealth University Richmond, Virginia, USA Running Title: Disrupted Mitobiogenesis Signaling in Alzheimer’s *Corresponding author: Ann C. Rice, Ph.D. Parkinson’s Disease Center Virginia Commonwealth University PO Box 980599 Richmond VA, 23298-0599 [email protected] ph: 804-828-9664 fax: 804-828-6373 1 Abstract Alzheimer’s disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP (+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 hr exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35, mtDNA copy numbers were not significantly altered. In summary, AD post-mortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD. 2 Keywords: laser capture microdissection, real-time PCR, neural stem cells, PGC1 alpha, TFAM 3 Background Alzheimer’s disease (AD) is the most common neurodegenerative disease of adults and the major cause of age-related dementia. Memory loss first appears in the disorder known as “mild cognitive impairment” (amnestic MCI) that progresses into AD dementia at a rate of ~15% per year. Biomarkers of MCI include reduced cerebral glucose accumulation with preserved oxygen uptake and increased brain tissue markers of oxidative stress [1, 2]. Progression into AD dementia is associated with further reductions of cortical glucose accumulation and reduced brain oxygen consumption [1, 2]. These observations suggest that the AD brain may be “starving” metabolically [3]. Studies of post-mortem tissue support impaired bioenergetic metabolism in AD that may play a role in the degenerative loss of hippocampal and cortical neurons. There is loss of activities of decarboxylase TCA enzyme complexes [2, 4-6] and reduced mitochondrial respiration, mitochondrial mass and expression of mitochondrial biogenesis (mitobiogenesis) genes in post-mortem AD brain tissue [5, 7]. Individual AD brain neurons have impaired cytochrome oxidase activity histochemically [6], are populated by deleted mitochondrial DNA (mtDNA) molecules [8] and have reduced expression of nuclear encoded respiratory genes [9] . Loss of cerebral glucose accumulation in MCI and later in AD dementia and direct indicators of impaired mitochondrial function in AD brains could occur from lowered glucose transport, impairment of glycolysis, reduced activities of mitochondrial oxidative decarboxylation in the TCA cycle, impaired mitochondrial respiration, or combinations of these processes. 4 Mitochondrial respiration involves many proteins encoded both from nuclear and mitochondrial DNA. A complex regulatory system ensures an appropriate coordinated expression from both genomes for both basal respiratory levels or stress-induced upregulation (for review see:[10-13] ). Nuclear respiratory (transcription) factors 1 and 2 (NRF1 and NRF2) activate transcription of nuclear-encoded respiratory genes and transcription factor A from mitochondria (TFAM). TFAM initiates transcription of the mitochondrial-encoded respiratory genes and has a role in maintaining the mtDNA copy number and stabilizing the mtDNA. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) is a coactivator for many mitobiogenesis-associated transcription factors including NRF1, NRF2 and estrogen-related receptor α (ERRα, associated with fatty acid oxidation). PGC1α plays a key role in responding to environmental changes, through both post-translational modifications and increased expression, to turn on mitobiogenesis [14]. Although the exact mechanism of how PGC1α upregulates expression of the nuclear transcription factors is not clear, increased expression of NRF1 and NRF2 and subsequent increased expression of TFAM are observed when PGC1α is overexpressed [15]. Additionally, PGC1α does bind with NRF1, NRF2 and ERRα and co-activates expression of their target genes resulting in significantly increased mitobiogenesis resulting in the label of the “master regulator”. The present study examines in more detail the status of mtDNA and the expression levels of select mitobiogenesis genes from post-mortem AD and control (CTL) tissue. We used laser capture microdissection (LCM) to isolate 5 hippocampal pyramidal neurons, GFAP(+) glia and dentate granule neurons and quantitative real-time multiplex PCR (qPCR) to demonstrate decreased mtDNA copy number in pyramidal neurons from AD compared to control (CTL) cases. We show a loss of correlation of mitobiogenesis factors cDNAs in whole hippocampal tissue compared to mtDNA copy numbers in AD pyramidal neurons, which is preserved in CTL cases. In CTL hippocampal tissue PGC1α expression levels significantly correlate or trend with expression of other mitobiogenesis genes, but this correlation is lost in AD tissue. Total hippocampal Aβ1-42 peptide levels from post-mortem tissue did not correlate with mtDNA copy numbers in any cell type in AD. Additionally, we could not induce the mtDNA copy number loss by exposing human H9 neural stem cells to the neurotoxic Aβ25-35 fragment. Methods Tissue/samples: Human brain tissue was obtained following autopsy and flash frozen. Hippocampi were obtained from the Brain Resource Facility at the University of Virginia. Cases consisted of 10 AD by clinical and pathological diagnosis (mean age 79.9, mean post-mortem interval 6hr, 6 female, 4 male) and 9 CTL clinically considered normal with no pathological abnormalities (mean age 63.2, mean post-mortem interval 8.45hr, 6 female, 3 male). Tissue was embedded in Cryostat mounting media and sliced at 10 µm. Ten to twelve slices were processed for RNA extraction using the miRNeasy kit from Qiagen following the manufacturer’s instructions. RNA integrity was evaluated using the BioRad Experion capillary electrophoresis system. RNA quality index (RQI) values were 6 between 6.7 and 9.5 [16]. Representative electropherograms are presented in supplemental figure 1. The RNA was converted to cDNA using BioRad i-script cDNA synthesis kit following the manufacturer’s instructions. These samples are referred to as whole tissue cDNA. Approximately 15 slices were processed for protein isolation for sandwich elisa for Aß1-42 using the kit from Invitrogen and following the manufacturer’s instructions. Additional slices were melted on uncoated slides for laser capture microdissection of hippocampal pyramidal neurons, glia and dentate granule cells. Laser Capture Microdissection (LCM): Slices were fixed in 70% Ethanol, hydrated, stained with methylene blue, dehydrated and cleared in xylene for identifying and capturing hippocampal pyramidal neurons and dentate gyrus granule cells. Hippocampal glia were identified immunohistochemically
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